Mechanistic insights into HIV-mediated heart failure with preserved ejection fraction

HIV介导的射血分数保留的心力衰竭的机制见解

• 批准号: 9476609
• 负责人: Hossein Ardehali
• 金额: $ 64.68万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9476609
• 关键词: Address; Adverse effects; Age; Aging; Animals; Antioxidants; CCR5 gene; Calcium; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cells; Chronic; Chronic Disease; Comorbidity; Defect; Development; Disease; Drug Targeting; EFRAC; Effectiveness; Exposure to; Failure; Functional disorder; Future; General Population; Genes; Genetic; Genetic Predisposition to Disease; HIV; HIV Infections; Health; Heart failure; Heterogeneity; Human; Immune; Immunologic Deficiency Syndromes; In Vitro; Incidence; Inflammation; Knowledge; Left Ventricular Ejection Fraction; Ligands; Macaca; Macaca mulatta; Measures; Mediating; Mitochondria; Modeling; Muscle Cells; Natriuretic Peptides; Pathogenesis; Pathologic; Pathology; Patients; Persons; Pharmaceutical Preparations; Predisposition; Reactive Oxygen Species; Relaxation; Reporting; Risk; Role; SIV; Soluble Guanylate Cyclase; Stimulus; System; Virus Replication; antiretroviral therapy; cGMP production; cell injury; clinically significant; cytokine; heart cell; improved; in vitro Model; induced pluripotent stem cell; inflammatory milieu; inhibitor/antagonist; insight; microbial; mitochondrial dysfunction; mortality; novel; novel therapeutics; phosphodiesterase V; transcriptome sequencing; treatment strategy

Persons living with HIV (PLWH) now live longer and suffer from many chronic conditions, which occur in PLWH at a higher rate and at an earlier age, and continue to develop despite suppressive antiretroviral therapy (ART). One of the abnormalities commonly found in PLWH is heart failure with preserved ejection fraction (HFpEF), defined as diastolic dysfunction with left ventricular ejection fraction of 50% or more. The development of HFpEF in the general population is associated with an increase in all-cause mortality, highlighting the clinical significance of this disorder. The cellular mechanism of HFpEF in PLWH is not totally understood, but chronic inflammation, genetic predisposition, and side effects of ART have been proposed. In this proposal, we will address the fundamental gap in knowledge of the mechanism of HIV-associated HFpEF using two systems: 1) already established model of isolated cardiomyocytes from rhesus monkey that mimic HFpEF pathology following CCR5 ligand exposure, and 2) human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We will then simulate chronic inflammation in vitro by treating the cells with cytokines or exposing them to an inflammatory milieu. Our central hypothesis is that mitochondrial pathogenetic mechanisms in cardiomyocytes are triggered by HIV-associated systemic inflammation to cause HFpEF, and that novel therapies can counter the cellular derangements. We also hypothesize that the heterogeneity of susceptibility to HFpEF is due to differences in genetic predilection to these pathologic mechanisms. To study our hypothesis, we propose two aims. In Aim 1, we will determine the pathogenetic mechanisms of HFpEF in cardiomyocytes. Isolated rhesus monkey cardiomyocytes and control hiPSC-CMs from five non-infected, non- HFpEF donors will be exposed to an in vitro model of chronic inflammation using three systems: 1) addition of CCR5 ligands, 2) microbial translocation, and 3) addition of non-CCR5 ligand cytokines, all of which have been demonstrated to be altered in PLWH independent of viral replication. We will then assess the effects of these manipulations on cardiomyocyte relaxation and function by measuring calcium transients, in addition to mitochondrial function and ROS (as markers of cellular injury). We will also treat hiPSC-CMs and isolated cardiomyocytes with ART to rule out a contribution of ART to diastolic dysfunction. Finally, we will generate hiPSC-CMs from 10 HIV patients, 5 with, and 5 without HFpEF and perform RNA-sequencing to identify candidate genes for characterization of the genetic basis of susceptibility to HFpEF. In Aim 2, we will determine whether novel drugs protect cardiomyocytes against the cellular pathogenesis causing HFpEF. We will expose cardiomyocytes from macaque and hiPSC-CMs to an inflammatory environment as described in Aim 1, and will assess whether treatment with drugs downstream of inflammation and ROS (i.e., phosphodiesterase 5/9 inhibitors, soluble guanylate cyclase stimulators, natriuretic peptides, and antioxidants) improve calcium transients and mitochondrial function.

患有艾滋病毒（PLWH）的人现在寿命更长，并且患有许多慢性病，这发生在PLWH中 以较高的速度和更早的年龄，尽管抑制性抗逆转录病毒疗法（ART）仍在继续发展。 PLWH中常见的异常之一是心力衰竭，保留的射血分数（HFPEF）， 定义为舒张功能障碍，左心室射血分数为50％或更多。 HFPEF的发展 在一般人群中，全因死亡率的增加有关，突出了临床意义 这种疾病。 PLWH中HFPEF的细胞机制尚不完全了解，而是慢性炎症， 已经提出了遗传倾向和艺术的副作用。在此提案中，我们将解决 使用两个系统了解与HIV相关的HFPEF机理的知识的基本差距：1） 来自恒河猴的孤立心肌细胞的建立模型，该模仿CCR5之后的HFPEF病理 配体暴露和2）人类诱导多能干细胞衍生的心肌细胞（HIPSC-CMS）。然后我们会 通过用细胞因子处理细胞或暴露于炎症，在体外模拟慢性炎症 环境。我们的中心假设是心肌细胞中的线粒体致病机制是 由HIV相关的全身性炎症引起的引起HFPEF，这种新型疗法可以 对抗细胞扰动。我们还假设易感性的异质性 HFPEF是由于遗传偏见对这些病理机制的差异。研究我们的 假设，我们提出了两个目标。在AIM 1中，我们将确定HFPEF的致病机制 心肌细胞。分离的恒河猴心肌细胞和来自五个未感染的非感染，非感染的HIPSC-CM HFPEF供体将使用三个系统暴露于慢性炎症的体外模型：1）添加 CCR5配体，2）微生物易位和3）添加非CCR5配体细胞因子，所有这些都已 证明在PLWH中与病毒复制无关。然后，我们将评估这些影响 通过测量钙瞬变来操纵心肌细胞放松和功能，此外 线粒体功能和ROS（作为细胞损伤的标记）。我们还将治疗HIPSC-CM和隔离 带有艺术的心肌细胞排除艺术对舒张功能障碍的贡献。最后，我们将生成 来自10名HIV患者的HIPSC-CM，5例，5例，无HFPEF，并进行RNA顺序以识别 候选基因，用于表征HFPEF易感性的遗传基础。在AIM 2中，我们将确定 新型药物是否保护心肌细胞免受导致HFPEF的细胞发病机制的影响。我们将暴露 如AIM 1所述，从猕猴和HIPSC-CM到炎症环境的心肌细胞，将 评估炎症和ROS下游的药物是否治疗（即磷酸二酯酶5/9 抑制剂，可溶性鸟苷酸环化酶刺激剂，脂肪肽和抗氧化剂）改善钙 瞬态和线粒体功能。